Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
BMC Med Genet. 2010 Feb 8;11:22. doi: 10.1186/1471-2350-11-22.
Previously we performed a linkage scan of 638 African American affected sibling pairs (ASP) with type 2 diabetes (T2D) enriched for end-stage renal disease (ESRD). Ordered subset linkage analysis (OSA) revealed a linkage peak on chromosome 7p in the subset of families with earlier age of T2D diagnosis.
We fine mapped this region by genotyping 11 additional polymorphic markers in the same ASP and investigated a total of 68 single nucleotide polymorphisms (SNPs) in functional candidate genes (GCK1, IL6, IGFBP1 and IGFBP3) for association with age of T2D diagnosis, age of ESRD diagnosis, duration of T2D to onset of ESRD, body mass index (BMI) in African American cases and T2D-ESRD in an African American case-control cohort. OSA of fine mapping markers supported linkage at 28 cM on 7p (near D7S3051) in early-onset T2D families (max. LOD = 3.61, P = 0.002). SNPs in candidate genes and 70 ancestry-informative markers (AIMs) were evaluated in 577 African American T2D-ESRD cases and 596 African American controls.
The most significant association was observed between ESRD age of diagnosis and SNP rs730497, located in intron 1 of the GCK1 gene (recessive T2D age-adjusted P = 0.0006). Nominal associations were observed with GCK1 SNPs and T2D age of diagnosis (BMI-adjusted P = 0.014 to 0.032). Also, one IGFBP1 and four IGFBP3 SNPs showed nominal genotypic association with T2D-ESRD (P = 0.002-0.049). After correcting for multiple tests, only rs730497 remanined significant.
Variant rs730947 in the GCK1 gene appears to play a role in early ESRD onset in African Americans.
我们之前对 638 对 2 型糖尿病（T2D）合并终末期肾病（ESRD）的非洲裔美国受影响同胞对（ASP）进行了连锁扫描。有序子集连锁分析（OSA）显示，在 T2D 诊断年龄较早的亚组家族中，染色体 7p 上存在连锁峰。
我们通过对相同 ASP 中的 11 个额外多态标记物进行基因分型，对该区域进行了精细映射，并对 68 个功能候选基因（GCK1、IL6、IGFBP1 和 IGFBP3）中的单核苷酸多态性（SNP）进行了全基因组关联分析，以研究其与 T2D 诊断年龄、ESRD 诊断年龄、T2D 至 ESRD 发病的时间、非洲裔美国人病例的体重指数（BMI）以及非洲裔美国人病例对照队列中的 T2D-ESRD 的关系。精细映射标记物的 OSA 支持早发性 T2D 家族中 7p 上 28cM 处的连锁（在 7p 上靠近 D7S3051 的最大 LOD = 3.61，P = 0.002）。候选基因和 70 个祖先信息标记物（AIMs）中的 SNP 在 577 名非洲裔美国 T2D-ESRD 病例和 596 名非洲裔美国对照中进行了评估。
最显著的关联是在 GCK1 基因内含子 1 中 rs730497 与 ESRD 诊断年龄之间观察到的（隐性 T2D 年龄调整后的 P = 0.0006）。GCK1SNP 与 T2D 诊断年龄之间观察到名义关联（BMI 调整后的 P = 0.014 至 0.032）。此外，一个 IGFBP1 和四个 IGFBP3SNP 与 T2D-ESRD 显示出名义的基因型关联（P = 0.002-0.049）。在进行多次检验校正后，只有 rs730497 仍然具有显著性。
GCK1 基因中的变体 rs730947 似乎在非洲裔美国人的早期 ESRD 发病中起作用。
